Unique aspects of the biology of HIV/SIV infection, including the use of immunologically functional CD4 as the receptor for infection of functional immune cells, the permanence of the infection due to integration into the host genome, and the mutability of these viruses pose great challenges for the development of a protective vaccine. Since a dominant protective immune mechanism remains unidentified, several potentially protective immune mechanisms must be considered and intensively studied simultaneously in order to fully understand the results of vaccine trials. Sexual transmission of cell-free an cell- associated virus to mucosal membranes is a major route of infection. Studies of mucosal immunity pose a particular problem because the process of mucosal infection and the mechanisms of immunity are not completely understood. Such studies are labor intensive and technically demanding, and require groups with diverse skills for their accomplishment. Two on- site groups will work in close collaboration to provide a comprehensive evaluation of systemic and mucosal immunity related to viral pathogenesis and protection. We will: 1) evaluated mucosal and systemic cell-mediated immunity including TH1/TH2 proportion and cytotoxic immune mechanisms such as cytotoxic T-lymphocytes (CTL), antibody-dependent cellular cytolysis (ADCC) and antibody complement cytotoxicity (ACC); 2) assess the induction of specific B-cells and plasma cells by various vaccines and adjuvants; and 3) compare different priming routes for induction of mucosal CTL. Through close interactions that have been established among these investigators, a composite view of the mucosal immune system should result from these studies.